A cardinal characteristic of malignant cells in vitro is lack of density-dependent inhibition of cell division (contact inhibition of growth) which benign cells exhibit. Loss of such in vitro growth control is directly related to in vivo tumorigenicity. The possibility that loss of this type of growth control reflects a genetic or epigenetic abnormality in malignant cell is implicit in mounting evidence that malignancy involves errors either in genetic information or expression of such information. This in turn implies the existence and participation of specific macromolecules in benign cells concerned with the maintenance of capacity for normal contact-inhibition of growth. A newly identified contact-inhibitory factor recently isolated from a contact-inhibited, benign blue nevus-transformed, hamster melanoma cell line, has been found for the first time to restore to malignant melanocytes the in vitro property of normal contact-inhibition of growth, and may be the prototype for a fundamental regulatory mechanism for control of normal mammalian cell interactions. It is proposed to study the origins, specificity, chemical characterization, and mechanisms of action of the contact-inhibitory factor, and to use this new and powerful investigative tool to help clarify the complex sequence of events involved in the establishment of the contact-inhibited state. Such studies are an essential prerequisite for eventual attempts to restore to malignant cells the capacity for normal growth control.